SK channel activation potentiates auranofin-induced cell death in glio- and neuroblastoma cells

Inge E Krabbendam*, Birgit Honrath, Laura Bothof, Eduardo Silva-Pavez, Hernán Huerta, Natalia M Peñaranda Fajardo, Frank Dekker, Martina Schmidt, Carsten Culmsee, Julio César Cárdenas, Frank Kruyt, Amalia M Dolga

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.

Original languageEnglish
Article number113714
Number of pages13
JournalBiochemical Pharmacology
Volume171
Early online date15-Nov-2019
DOIs
Publication statusPublished - Jan-2020

Keywords

  • OXIDATIVE STRESS
  • ION CHANNELS
  • MITOCHONDRIAL RESPIRATION
  • K+ CHANNELS
  • CANCER
  • THIOREDOXIN
  • APOPTOSIS
  • INHIBITION
  • INDUCTION
  • TUMOR

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